Goh C.L.,The Institute of Cancer Research |
Schumacher F.R.,University of Southern California |
Easton D.,Cancer Research Center for Cancer Genetic Epidemiology |
Easton D.,University of Cambridge |
And 5 more authors.
Journal of Internal Medicine | Year: 2012
Prostate cancer is the commonest cancer in the developed world. There is an inherited component to this disease as shown in familial and twin studies. However, the discovery of these variants has been difficult. The emergence of genome-wide association studies has led to the identification of over 46 susceptibility loci. Their clinical utility to predict risk, response to treatment, or treatment toxicity, remains undefined. Large consortia are needed to achieve adequate statistical power to answer these genetic-clinical and genetic-epidemiological questions. International collaborations are currently underway to link genetic with clinical/epidemiological data to develop risk prediction models, which could direct screening and treatment programs. © 2012 The Association for the Publication of the Journal of Internal Medicine.
Larkin J.,Royal Marsden Foundation NHS Trust |
Hatswell A.J.,BresMed |
Nathan P.,Mount Vernon Cancer Center |
Lebmeier M.,Bristol Myers Squibb |
PLoS ONE | Year: 2015
Background: Evaluating long-term prognosis is important for physicians, patients and payers. This study reports the results of a model developed to predict long-term survival for UK patients receiving second-line ipilimumab. Methods: MDX010-20 trial data were used to predict survival for ipilimumab versus UK best supportive care. Two aspects of this analysis required novel approaches: 1) The overall survival Kaplan-Meier data shape is unusual: an initial steep decline is observed before a 'plateau'. 2) The need to extrapolate beyond the trial end (4.6 years). Based upon UK clinician advice, a three-part curve fit was used: from 0-1.5 years, Kaplan-Meier data from the trial; from 1.5-5 years, standard parametric curve fits; after 5 years, long-term data from the American Joint Committee on Cancer registry. Results: This approach provided good internal validity: low mean absolute error and good match to median and mean trial data. Lifetime predicted means were 2.77 years for ipilimumab and 1.07 for best supportive care, driven by increased long-term survival with ipilimumab. Conclusion: To understand the full benefit of treatment and to meet reimbursement requirements, accurate estimation of treatment benefit is key. Models, such as the one presented, can be used to extrapolate beyond trials. © 2015 Larkin et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Pacey S.,Cancer Research UK Research Institute |
Wilson R.H.,Queen's University of Belfast |
Walton M.,Cancer Research UK Research Institute |
Eatock M.M.,Queen's University of Belfast |
And 19 more authors.
Clinical Cancer Research | Year: 2011
Purpose: A phase I study to define toxicity and recommend a phase II dose of the HSP90 inhibitor alvespimycin (17-DMAG; 17-dimethylaminoethylamino-17- demethoxygeldanamycin). Secondary endpoints included evaluation of pharmacokinetic profile, tumor response, and definition of a biologically effective dose (BED). Patients and Methods: Patients with advanced solid cancers were treated with weekly, intravenous (i.v.) 17-DMAG. An accelerated titration dose escalation design was used. The maximum tolerated dose (MTD) was the highest dose at which ≤1/6 patients experienced dose limiting toxicity (DLT). Dose de-escalation from the MTD was planned with mandatory, sequential tumor biopsies to determine a BED. Pharmacokinetic and pharmacodynamic assays were validated prior to patient accrual. Results: Twenty-five patients received 17-DMAG (range 2.5-106 mg/m2). At 106 mg/m2 of 17-DMAG 2/4 patients experienced DLT, including one treatment-related death. No DLT occurred at 80 mg/m2. Common adverse events were gastrointestinal, liver function changes, and ocular. Area under the curve and mean peak concentration increased proportionally with 17-DMAG doses 80 mg/m2 or less. In peripheral blood mononuclear cells significant (P < 0.05) HSP72 induction was detected (≥20 mg/m2) and sustained for 96 hours (≥40 mg/m2). Plasma HSP72 levels were greatest in the two patients who experienced DLT. At 80 mg/m2 client protein (CDK4, LCK) depletion was detected and tumor samples from 3 of 5 patients confirmed HSP90 inhibition. Clinical activity included complete response (castration refractory prostate cancer, CRPC 124 weeks), partial response (melanoma, 159 weeks), and stable disease (chondrosarcoma, CRPC, and renal cancer for 28, 59, and 76 weeks, respectively). Couclusions: The recommended phase II dose of 17-DMAG is 80 mg/m2 weekly i.v. ©2011 AACR.
Pacey S.,Cancer Research UK Research Institute |
Pacey S.,Royal Marsden Foundation NHS Trust |
Gore M.,Royal Marsden Foundation NHS Trust |
Chao D.,Royal Free Hospital |
And 12 more authors.
Investigational New Drugs | Year: 2012
Purpose A Phase II study to screen for antimelanoma activity of the heat shock protein 90 (HSP90) inhibitor, 17-AAG (17-allylamino-17- demethoxygeldanamycin) was performed. The primary endpoint was the rate of disease stabilisation in patients with progressive, metastatic melanoma treated with 17-AAG. Secondary endpoints were to determine: the toxicity of 17-AAG, the duration of response(s), median survival and further study the pharmacokinetics and pharmacodynamics of 17-AAG. Patients and Methods Patients with metastatic melanoma (progressive disease documented ≤6 months of entering study) were treated with weekly, intravenous 17-AAG. A Simon one sample two stage minimax design was used. A stable disease rate of ≥25% at 6 months was considered compatible with 17-AAG having activity. Results Fourteen patients (8 male: 6 female) were entered, eleven received 17-AAG (performance status 0 or 1). Median age was 60 (range 29-81) years. The majority (93%) received prior chemotherapy and had stage M1c disease (71%). Toxicity was rarely ≥ Grade 2 in severity and commonly included fatigue, headache and gastrointestinal disturbances. One of eleven patients treated with 17-AAG had stable disease for 6 months and median survival for all patients was 173 days. The study was closed prematurely prior to completion of the first stage of recruitment and limited planned pharmacokinetic and pharmacodynamic analyses. Conclusion Some evidence of 17-AAG activity was observed although early study termination meant study endpoints were not reached. Stable disease rates can be incorporated into trials screening for anti-melanoma activity and further study of HSP90 inhibitors in melanoma should be considered. © Springer Science+Business Media, LLC 2010.
O'Mmahoney E.,Smithfield Trust |
Murray I.,Royal Marsden Foundation NHS Trust
Nuclear Medicine Communications | Year: 2013
AIM: The aim of our study was to assess improvements in spatial resolution and noise control from the application of the Astonish resolution recovery algorithm for single photon emission computed tomography imaging. Secondary aims were to compare acquisitions made with low-energy general purpose collimators with those obtained using low-energy high-resolution collimators in this context and evaluate the potential of a finer matrix to improve image quality further. MATERIALS AND METHODS: A Tc-filled Jaszczak phantom with hot spheres was used to assess contrast and noise. A National Electrical Manufacturers Association triple line source single photon emission computed tomography resolution phantom was used to measure spatial resolution. Acquisitions were made using both low-energy high-resolution and low-energy general purpose collimators. RESULTS: Compared with standard ordered subsets expectation maximization reconstructions, the resolution recovery algorithm resulted in a higher spatial resolution (8 vs. 14 mm full-width at half-maximum) leading to reduced partial volume effects in the smaller Jaszczak spheres. Higher image contrast was achieved alongside lower levels of noise. An edge enhancement artefact was observed in the resolution recovery corrected images. An overestimate of the target-to-background activity was also observed for the larger spheres. CONCLUSION: The use of such an algorithm results in images characterized by increased spatial resolution and reduced noise. However, small sources of the order of 2-3 cm can be significantly overenhanced. © 2013 Wolters Kluwer Health | Lippincott Williams & Wilkins.